GENETIC CHANGES AND HUMAN DISEASE
SINGLE NUCLEOTIDE SUBSTITUTIONS
A substitution that conserves the base chemistry C-T, T-C, G-A, A-G
A substitution that changes the base chemistry C-A, A-C, G-C, C-G, A-T, T-A, G-T, T-G
Although there are twice as many transversions possible as transitions, it is found that transitions are roughly twice as lucky as transversions.
A loss of a single base or a continuous block of sequence
An insertion of a single base or a continuous block of sequence between two previously adjacent bases.
TANDEM DUPLICATION (INSERTION) A special type of insertion where the inserted material is identical to the adjacent sequence.
A block of sequence is inverted and replaced with its reverse compliment - from tgggtcgc to gcgaccca!!
May be benign.
Movement of sequences of DNA between two different chromosomes.
May be benign.
Do not affect the protein directly, may affect splicing.
MISSENSE Will cause a single amino acid change which may have neutral or harmful effects.
Causes premature termination of the reading frame, resulting in a truncated protein.
MULLERS MORPHS AMORPH: variant with complete loss of gene function
HYPOMORPH: variant causing partial loss of gene function
HYPERMORPH: variant causing an increase in normal gene function
ANTIMORPH: dominant alleles that act in opposition to normal gene activity
NEOMORPH: variant that cause a dominant gain in gene function different to the normal function
TYPES OF LOSS OF FUNCTION ALLELES EXHIBITING A DOMINANT FORM OF INHERITANCE
Organism so sensitive to levels of the protein that a 50% reduction in quantity causes a noticeable phenotype.
DOMINANT NEGATIVE EFFECT
Formation of the homomultimeric complexes means that not only does the protein lose its function, but disrupts the function of its normal counterpart.
SOMATIC SECOND HITS
Organism is largely normal, but somatic second mutations give rare clones of null cells, which are defective. Recessive at the cellular level but dominantly inherited in families.
TYPES OF GAIN OF FUNCTION DOMINANTLY INHERITED
LOSS OF REGULATION
The activity of the protein loses its spatial or temporal specificity, due to the loss of a regulatory region or dislocation.
NOVEL FUNCTION Protein has a novel effect which is not characteristic of the normal product, a common novel “function” is formation of insoluble aggregates.
INFANTILE ONSENT EPILEPSY IN THE AMISH
SIAT9 gene encodes GM3 synthase - needed for a- and b- gangliosides needed for membrane stability, the mutation causes loss of function of GM3 synthase.